BUB3

918412237ENSG00000154473ENSMUSG00000066979O43684Q9WVA3NM_004725NM_001007793NM_009774NM_001317350NP_001007794NP_004716NP_001304279NP_033904Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene. Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene. Bub3 is a protein involved with the regulation of the Spindle Assembly Checkpoint (SAC); though BUB3 is non-essential in yeast, it is essential in higher eukaryotes. As one of the checkpoint proteins, Bub3 delays the irreversible onset of anaphase through direction of kinetochore localization during prometaphase to achieve biorentation. In directing the kinetochore-microtubule interaction, this ensures the proper (and consequenctly, bioriented) attachment of the chromosomes prior to anaphase. Bub3 and its related proteins that form the Spindle Assembly Checkpoint (SAC) inhibit the action of the Anaphase Promoting Complex (APC), preventing early anaphase entry and mitotic exit; this serves as a mechanism for the fidelity of chromosomal segregation. Bub3 is a crucial component in the formation of the mitotic spindle assembly complex, which forms a complex with other important proteins. For correct segregation of the cells it is necessary for all mitotic spindles to attach correctly to the kinetochore of each chromosome. This is controlled by the mitotic spindle checkpoint complex which operates as a feedback-response. If there is a signal of a defect in the attachment, mitosis will be stopped to ensure that all chromosomes have an amphitelic binding to spindles. After the error is corrected, the cell will proceed to anaphase. The complex of proteins which regulate the cell arrest are BUB1, BUB2, BUB3 (this protein), Mad1, Mad2, Mad3 and MPS1. At unattached kinetochores, a complex consisting of BubR1, Bub3, and Cdc20 interact with the Mad2-Cdc20 complex to inhibit the APC, thus inhibiting the formation of active APCCdc20. Bub3 binds constitutively to BubR1; in this arrangement, Bub3 acts as a key component of the SAC in the formation of an inhibitory complex. Securin and cyclin B are also stabilized before the anaphase transition by the unattached kinetochores. The stabilization of cyclin and securin prevent the degradation that would lead to the irreversible and fast separation of the sister chromatids. The formation of these “inhibitory complexes” and steps feed into a ‘wait’ signal before activation of separase; at the stage prior to anaphase, securin inhibits the activity of separase and maintains the cohesion complex. The crystal structure of Bub3 indicates a protein of the seven-bladed beta-propeller structure with the presence of WD40 repeats, with each blade formed by four anti-parallel beta sheet strands that have been organized around a tapered channel. Mutation data suggest several important surfaces of interaction for the formation of the SAC, particularly the conserved tryptophans (in blades 1 and 3) and the conserved VAVE sequences in blade 5. Rae1 (an mRNA export factor), another member of the WD40 protein family, shows high sequence conservation with that of Bub3. Both bind to Gle2p-binding-sequence (GLEBS) motifs; while Bub3 specifically binds Mad3 and Bub1, Rae1 has more promiscuous binding as it binds both the nuclear pore complex and Bub1. This indicates a similarity in interaction of Bub3 and Rae1 with Bub1. BUB3 has been shown to interact with BUB1B, HDAC1 and Histone deacetylase 2. Bub3 has been shown to form complexes with Mad1-Bub1 and with Cdc20 (the interaction of which does not require intact kinetochores). Additionally, it has been shown to bind Mad2 and Mad3.